Naturally occurring peptidyl nucleosides have long been investigated as antitumor as well as antimicrobial agents. Among those known for having these properties are cryschandin (Yamashita, M. et al., Chryscandin, A novel peptidyl nucleoside antibiotic. I. Taxonomy, fermentation, isolation and characterization. J. Antibiotics (1984), 37:1279-1283), L-homocitrullylaminoadenosine (Kredich, N. M. et al., Homocitrullyl-aminoadenosine, a nucleoside isolated from Cordyceps militaris. J. Biol. Chem. (1961) 236:3300-3302), L-lysylamino-adenosine (Shiao, M. et al., Natural products in Cordyceps. Proc. Natl. Sci. Counc. ROC(A) (1989) 13:382-387), and the more recently discovered cystocin (Lee, H. et al., Cystocin, a novel antibiotic, produced by Streptomyces sp. GCA0001: biological activities. Arch. Pharm. Res. (2003) 26:446-448).
Puromycin, produced by Streptomyces alboniger, is the best known member of this class. It mimics the aminoacyl-adenyl terminus of aminoacyl-tRNA, acting as a substrate of peptidyl transferase (Herris, R. J. et al., Molecular mechanism of protein biosynthesis. Ed. Weissbach, H.; and Pestka, S., Academic Press Inc, 413-442 (1977); Harris, R. J. et al., Peptide bond formation on the ribosome. Structural requirements for inhibition of protein synthesis and of release of peptides from peptidyl-tRNA on bacterial and mammalian ribosome by aminoacyl and nucleotidyl analogues of puromycin. Biochim. Biophys. Acta (1971) 240:244-262). Puromycin's incorporation into the growing peptide causes the growing chain to terminate prematurely, releasing an incomplete protein.
A number of natural peptidyl nucleoside antibiotics share similar properties with puromycin. Widely used as a basic tool in biochemistry and molecular biology, puromycin has been evaluated as an antimicrobial and antitumor agent with disappointing results. As an anticancer agent, the major drawback of puromycin is characteristic nephrotoxicity due to metabolism to puromycin amino nucleoside (PAN) (Borowsky, B. A. et al., Structural analogues of puromycin in production of experimental nephrosis in rats. Proc. Soc. Exp. Biol. Med. (1958) 97:857-860), which is demethylated in the liver (Derr, R. F. et al., Metabolism of puromycin aminonucleoside in the normal, “pre-nephrotic,” and nephrotic rat. Proc. Soc. Exp. Biol. Med. (1967) 125:248-252; Dickie, N. et al., Inhibition of adenosine deaminase by a metabolite of the nephrotoxic drug, puromycin aminonucleoside. Proc. Soc. Exp. Biol. Med. (1966) 123:421-423) and then phosphorylated to the toxic metabolite 3′-amino-3′-deoxy-N6-methyladenosine phosphate (Kmetec, E. et al., Metabolism of puromycin aminonucleoside in the rat. Formation of nucleotide derivatives. Biochem. Pharmacol. (1970) 19:1493-1500).
What are needed are metabolically stable, modified peptidyl nucleosides that have anti-tumor activity but that are metabolically stable and pharmaceutical compositions comprising the modified nucleosides.